VASOPRESSIN AND THE REGULATION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXISFUNCTION - IMPLICATIONS FOR THE PATHOPHYSIOLOGY OF DEPRESSION

The role of arginine vasopressin (AVP/VP) in the control of adrenocort icotropic hormone (ACTH) secretion is explored, and in particular, its involvement in various stress response paradigms which may be of rele vance in our understanding of the pathophysiology of depression. VP is released from two sites in the hypothalamus; the parvicellular divisi on of the paraventricular nucleus (PVN), where corticotropin releasing hormone (CRH) is also formed, and from the magnocellular neurons of t he supraoptic nucleus (SON) and the PVN. The intricate interaction wit h CRH, the other main ACTH secretagogue, and with glucocorticoids, the inhibitory feedback component of hypothalamic-pituitary-adrenal -axis (HPA) activity, is outlined. That VP plays an important role in the s tress response is now beyond doubt. Examination of the impact of psych ological stressors on the differential expression of VP and CRH at a h ypothalamic and pituitary level has been facilitated by advances in mo lecular biological techniques. Of importance has been the cloning of t he V-1b receptor gene, the receptor at which AVP is active in the ante rior pituitary. Chronic stress paradigms, associated with HPA hyperres ponsiveness, and ACTH release following a novel superimposed stress, h ave been found with relative consistency to show a shift in the CRH:AV P ratio. This may relate to differing feedback sensitivity of AVP to g lucocorticoid feedback restraint and the greater responsivity of AVP o ver CRH to chronic stimulatory stress input. Evidence for functionally distinct pools of ACTH releasing corticotropes, and the finding that AVP levels more closely correlate with ACTH levels than do CRH levels, suggest a more dynamic role for AVP in activity of the stress axis, a nd a primarily permissive function for CRH. The renewed interest in th e role of VP in HPA axis activity may have important implications for furthering our understanding of psychiatric conditions such as depress ion, where significant dysregulation of this axis is seen. Elevated ba seline cortisol, dexamethasone non-suppression and blunted CRH/ACTH re lease have been consistently documented. The possible contribution of VP to this hyperactivity, despite its known synergy with CRH, has been largely neglected. In animal models there is clear evidence that chro nic psychological stressors increase the ratio of AVP to CRH productio n. Psychosocial stressors are intrinsically linked with depressive ill ness. The finding of elevated levels of AVP in postmortem studies of d epressives and the lowering of CSF AVP levels by antidepressants, rais es the question of the precise role of AVP in the overactivity of the HPA in depression, a finding that is currently attributed to overdrive of its HPA regulatory companion, CRH.